1. Field of the Invention
This invention is directed to support systems and containers for lyophilization and methods for lyophilization with flexible containers.
2. Description of the Background
Fresh Frozen Plasma (FFP) is essential for the clinical management of coagulopathies associated with combat trauma. However, the frozen formulation has three major limitations, which reduce its far forward availability in the field. First, FFP must be stored at −30° C. in freezers. Second, the number of FFP units transshipped is restricted by the dry ice (CO2) limitation of air transport. And finally, this creates a need for bulky and expensive processing equipment along with sufficient time to properly thawed the units before transfusion. Processing times are typically from 30 to 40 minutes, but can on occasion be longer.
Several containers have been recently introduced, which permit lyophilization of products to take place in an enclosed system omitting the risk of contamination during the lyophilization process and in line with FDA requirements for blood processing (FIGS. 1-5). Such containers commonly feature hydrophobic protective membranes. The membranes contain pores, which are permeable to water vapor but, on the other hand, are sufficiently small (<0.2 μm) so as to prevent microorganisms from passing through. Membrane permeability to water vapor permits product drying inside these closed containers. Membrane impermeability to microorganisms adds a protective feature to these containers to classify them as enclosed systems. Membrane impermeability to fluids makes these containers suitable for direct rehydration.
These containers come in two basic formats: flexible (FIGS. 1, 2) and rigid (FIGS. 3-5). Rigid containers feature solid side walls and possess the required stability to withstand the stress of freeze-drying, particularly the strain imposed by the vacuum during the process. These containers, however, cannot be collapsed after completion of the lyophilization process. Flexible containers, on the other hand, typically feature a pliable bottom wall, a pliable top wall incorporating a breathable membrane, and side walls sufficiently rigid to support the top wall, but also sufficiently flexible to collapse and minimize storage space once lyophilization is complete (FIG. 1). The container structure is intended to be sufficiently rigid to sustain the stress imposed by the lyophilization process, but is also flexible enough to be collapsed after lyophilization, thereby reducing storage space and offering a logistical advantage.
U.S. Pat. No. 6,517,526 (which is entirely and specifically incorporated by reference) relates to a lyophilization system and discloses a thermally conductive tray which serves as its support system. The tray defines at least one cavity having a cavity floor and a depth that accommodates the lyo-container. The support system further includes a rigid mating flange, which overlays the supporting tray, cooperating with the tray, to secure landing of the lyo-container during lyophilization. Although this support system allows for handling of the container in a more convenient way, it is neither intended to prevent folding of the flexible bottom under vacuum, nor to assure a flat fixture of the top pliable membrane prior to or during lyophilization.
A flexible container developed by Foster-Miller Corp. features a supportive system. That system contains a plastic rigid internal ring on top of which is secured a pliable membrane. The rigid ring assures a flat fixed shape of the pliable membrane prior to and during lyophilization. However, removing the ring from the internal container structure is required to collapse the container after lyophilization and to take advantage of its flexible nature, although this latter process is not clearly defined.
To remedy the storage, shipment and processing problems and to bring plasma far forward in the field, a freeze-dried whole plasma product stable at ambient temperature was developed. The process of plasma lyophilization is carried out in glass bottles in an open space environment. However, at least two problems are associated with these containers that obstruct their successful realization in the hospital and/or the field. First, the containers are glass and glass, although rigid, is not a blood bank/hospital compatible container and cannot be used in transfusion practice. Second, product processing and lyophilization typically occur in an open space environment thus exposing the product to contaminants. However, FDA regulations do not permit blood processing in an open environment.
A container for plasma lyophilization called the lyo-bag was developed by Circulatory Technology Inc. (FIGS. 1-2). However, two problems associated with the container structure (FIG. 2) inhibited its successful utilization. First, the side walls of the container do not provide sufficient support to the top membranous wall. As a result, the flexible membrane collapses over the fluid in the container before and/or during the process of lyophilization as vacuum stresses the container. Contamination of the breathable membrane with the product blocks its porous structure and inhibits water vapor removal through it, resulting in a partially dried product (FIG. 3).
Also, the flexible bottom wall folds upwards during the process of lyophilization, particularly, as vacuum is applied to the system. The folded flexible bottom wall no longer provides an intimate thermal contact with the cooling/heating shelf of the freeze-dryer. As a consequence, pockets with incompletely dried product are formed (FIG. 4), which renders the resulting material useless. Thus, a need exists for suitable containers for plasma lyophilization.